Amoxicillin preparation and preparation method thereof

Abstract

The invention provides an amoxicillin preparation and a preparation method thereof, and the preparation method comprises the following steps: preparing a temperature-sensitive polymer solution, uniformly mixing amoxicillin powder with chitosan and pretreated lactose, adding the mixture into the temperature-sensitive polymer solution, and carrying out spray drying to form amoxicillin-polymer composite particles, and carrying out multi-layer temperature sensitive coating treatment and curing. According to the invention, by using the temperature-sensitive polymer PNIPAM, the drug can be quickly released at an inflammation part under a high-temperature condition, the drug effect is improved, and the side effect is reduced. Due to the addition of the chitosan and the pretreated lactose, the solubility and bioavailability of the amoxicillin are improved, and the uniform distribution and sustained release of the medicine are ensured. The use of the plasticizer glycerol enhances the flexibility and stability of the polymer, and through curing treatment, the stability of the coating layer and the controllability of drug release are improved. The amoxicillin preparation disclosed by the invention has remarkable advantages in the aspects of improving the curative effect, reducing the side effect and improving the compliance of a patient.

Description

Technical Field

[0001] The present invention relates to the technical field of amoxicillin, in particular to an amoxicillin preparation and a preparation method thereof. Background Art

[0002] In the pharmaceutical field, effective drug delivery systems are crucial to improving treatment efficacy and patient compliance. Amoxicillin, as one of the most widely used antibiotics, is often used to treat various bacterial infections, such as respiratory tract, urinary tract and skin infections. However, traditional amoxicillin formulations such as tablets or conventional capsules have some limitations, including the need for frequent dosing to maintain the therapeutic effect, as well as potential side effects, such as gastrointestinal discomfort.

[0003] With the deepening of medical research, controlled release technology has become an important field of drug development. Controlled release preparations can prolong the duration of drug action in the body, reduce the number of dosing times, improve patient compliance, and reduce or avoid side effects. At present, there are many controlled release preparations on the market, such as microcapsules, nanoparticles, multi-layer coatings, etc., which achieve the effect of controlled release by changing the dynamics of drug release.

[0004] However, these existing controlled-release technologies are generally not environmentally sensitive, that is, they cannot adjust the drug release rate according to changes in the body environment (such as pH or temperature changes). Especially at the site of inflammation, the body temperature is often higher than normal body temperature, which provides application prospects for temperature-sensitive drug release systems. Temperature-sensitive controlled-release preparations can remain stable at normal body temperature and quickly release drugs at higher temperatures at the site of inflammation, thereby achieving targeted therapy, improving drug efficacy and reducing systemic side effects. Existing temperature-sensitive preparations often fail to respond quickly when the trigger temperature is reached, which may affect the efficacy and safety of the drug. This requires a new formulation design to ensure that the drug is released quickly and accurately when necessary, while remaining stable under conventional storage conditions. Summary of the invention

[0005] Existing controlled-release technologies are generally not environmentally sensitive, that is, they cannot adjust the drug release rate according to changes in the body environment (such as pH or temperature changes). Especially at the site of inflammation, the body temperature is often higher than normal body temperature, which provides application prospects for temperature-sensitive drug release systems. Temperature-sensitive controlled-release preparations can remain stable at normal body temperature and quickly release drugs at higher temperatures at the site of inflammation, thereby achieving targeted therapy, improving drug efficacy and reducing systemic side effects. Existing temperature-sensitive preparations often fail to respond quickly when the trigger temperature is reached, which may affect the efficacy and safety of the drug. This requires a new formulation design to ensure that the drug is released quickly and accurately when necessary, while remaining stable under conventional storage conditions.

[0006] The present application provides a method for preparing an amoxicillin preparation, comprising the following steps:

[0007] S1. Prepare temperature-sensitive polymer solution: dissolve PNIPAM in deionized water, add MBAA, stir evenly to form a uniform temperature-sensitive polymer solution, then add plasticizer, continue stirring to ensure uniform mixing; S2. Evenly mix amoxicillin powder with chitosan and pretreated lactose, and then gradually add them to the temperature-sensitive polymer solution, continue stirring to ensure uniform dispersion, and spray dry the mixed solution to form amoxicillin-polymer composite particles; S3. Use a fluidized bed to coat the amoxicillin-polymer composite particles to form a multi-layer temperature-sensitive coating layer; S4. Curing the coated particles at 40°C and 75% relative humidity for 4 hours to improve the stability of the coating layer and the controllability of drug release.

[0008] By adopting the above technical solution, poly (N-isopropylacrylamide) (PNIPAM) is a temperature-sensitive polymer whose solubility changes with temperature, achieving temperature-sensitive controlled release, and rapidly changing its structure to release drugs when body temperature rises. By adding a cross-linking agent (N, N'-methylenebisacrylamide, MBAA), a stable three-dimensional cross-linked network is formed in the temperature-sensitive polymer, which can significantly enhance the mechanical strength, thermal stability and swelling behavior control of the drug preparation, thereby achieving better drug release control effects. These technical effects make the cross-linking agent play a vital role in temperature-sensitive drug preparations, ensuring that the preparations release drugs quickly and accurately when necessary. At the same time, it remains stable under conventional storage conditions. The amoxicillin powder is evenly mixed with chitosan and pretreated lactose. The pretreatment of lactose improves the dispersibility of amoxicillin in the preparation, ensures uniform distribution during the mixing process, and improves the overall quality and efficacy of the preparation. The synergistic effect of chitosan and amoxicillin can significantly improve the efficacy and stability of amoxicillin preparations. Chitosan, as a drug carrier, can not only enhance the solubility and bioavailability of amoxicillin, but also achieve controlled release and prolong the drug action time, thereby improving the therapeutic effect and reducing side effects. Through multiple temperature-sensitive coating layers, it is ensured that the drug is stable at normal temperature and is quickly released under high temperature conditions, thereby improving the therapeutic effect.

[0009] As a preferred technical solution of the preparation method of an amoxicillin preparation, the plasticizer is glycerol.

[0010] By adopting the above technical solution, glycerol forms hydrogen bonds with polymer chains through the hydroxyl groups in its molecular structure, reducing cohesion and enhancing interchain sliding, thereby exerting a plasticizing effect; at the same time, the hygroscopicity and moisturizing properties of glycerol further improve the stability and processing performance of the preparation.

[0011] As a preferred technical solution of the preparation method of an amoxicillin preparation, in step S2, the step of lactose pretreatment includes the following:

[0012] Dissolve lactose in an appropriate amount of deionized water, add citric acid at a mass ratio of 1:10 between citric acid and lactose, stir until completely dissolved, place the solution in an ultrasonic processor, and perform ultrasonic treatment for 30 minutes; wherein the ultrasonic frequency is set to 20-40kHz and the power is 200-400W;

[0013] Add 0.5-2wt% of lecithin particles to the lactose-citric acid solution, continue stirring for 30 minutes, and filter the lactose-citric acid-lecithin solution through a vacuum filtration device to remove undissolved impurities and large particles;

[0014] The filtrate was concentrated to 1 / 3 of the original volume using a rotary evaporator at a temperature below 50°C to further increase the concentration of the solution, and the concentrated solution was placed in a vacuum freeze dryer for freeze drying; wherein the freeze drying conditions were set as follows: freezing temperature -40°C, drying temperature -20°C, vacuum degree 0.01 mbar, and drying time 24 hours;

[0015] The dried powder is placed in a high-speed centrifuge and centrifuged at 10,000 rpm for 30 minutes to further remove possible free nanoparticles to ensure the purity of the final product; the dried lactose-citric acid-lecithin complex is crushed into a uniform fine powder by grinding or mechanical crushing, and sieved using sieves of different mesh sizes to ensure uniform particle size.

[0016] By adopting the above technical scheme, citric acid, as a chelating agent, can form a complex with lactose molecules, enhance the solubility of lactose in water, prevent lactose from crystallizing and precipitating in the solution, and improve the stability of the solution. Ultrasonic treatment can produce high-frequency vibration and cavitation effect, which is helpful to evenly disperse lactose particles in the solution, and can effectively remove bubbles in the solution to prevent the formation of pores in the subsequent treatment process. Lecithin reduces the surface tension of the solution, promotes the uniform dispersion of lactose particles in the solution, and prevents particle aggregation, further improving the uniformity and stability of the solution. Vacuum filtration removes undissolved impurities and large particles to ensure the purity of the solution and obtain a uniform and pure lactose-citric acid-lecithin solution. Rotary evaporation removes water by heating and rotating to concentrate the solution, further increase the concentration of the solution, and avoid high temperature damage to the lactose complex. Freeze drying removes water in the solution by rapid freezing and sublimation to form a dry powder, maintains the structure and functionality of the lactose complex, and prevents thermal degradation. The pulverization process refines the dried complex powder, and screening ensures uniform particle size to obtain a powder with uniform particle size, thereby improving its performance in the preparation.

[0017] As a preferred technical solution for the preparation of an amoxicillin preparation, lactose accounts for 5 to 9 wt % of the mass of deionized water.

[0018] By adopting the above technical solution, the amount of lactose added is optimized.

[0019] As a preferred technical solution for the preparation of an amoxicillin preparation, in step S1, the mass ratio between PNIPAM and MBAA is 10:1, and PNIPAM accounts for 15 to 20 wt % of the mass of deionized water.

[0020] By adopting the above technical scheme, the addition amounts of PNIPAM and MBAA are optimized to form a stable three-dimensional cross-linked network, which can significantly enhance the mechanical strength, thermal stability and swelling behavior control of the drug preparation, thereby achieving better drug release control effect.

[0021] As a preferred technical solution for the preparation of an amoxicillin preparation, in step S2, the mass ratio of amoxicillin powder, chitosan and pretreated lactose is 9:1:1.

[0022] By adopting the above technical solution, the mass ratio among amoxicillin powder, chitosan and pretreated lactose is optimized.

[0023] The amoxicillin preparation prepared by the above preparation method, and the outer side of the amoxicillin preparation coated with multiple temperature-sensitive coating layers, has been significantly improved in terms of drug release control, improved stability, reduced side effects, prolonged action time, and improved bioavailability. These technical effects ensure the high efficiency and reliability of the drug in practical applications, and provide an effective solution for the design of drug preparations such as amoxicillin.

[0024] The present invention has the following technical effects:

[0025] 1. Through step S1, PNIPAM is dissolved in deionized water, MBAA is added, and stirred evenly to form a uniform temperature-sensitive polymer solution, and then a plasticizer is added, and stirring is continued to ensure uniform mixing. Through step S3, amoxicillin-polymer composite particles are coated using a fluidized bed to form a multi-layer temperature-sensitive coating layer, thereby realizing a temperature-sensitive controlled-release system. The solubility of the temperature-sensitive polymer PNIPAM changes with changes in temperature, and the multi-layer coating layer further ensures that the drug can be released rapidly under high temperature conditions. This design enables the drug to be released quickly at the site of inflammation where the body temperature is elevated, while remaining stable at normal body temperature, thereby achieving targeted treatment. Through this temperature-sensitive controlled-release system, the concentrated release of the drug at the site of inflammation is improved, the efficacy is enhanced, and systemic side effects are reduced, ensuring that the drug can be adaptively released according to the patient's internal environment, thereby improving the accuracy and effectiveness of the treatment;

[0026] 2. Through step S2, the amoxicillin powder is evenly mixed with chitosan and pretreated lactose, and then gradually added to the temperature-sensitive polymer solution, and stirring is continued to ensure uniform dispersion. The mixed solution is spray-dried by spray drying to form amoxicillin-polymer composite particles. Combined with the lactose pretreatment of step S2, the lactose is dissolved in deionized water, citric acid is added, ultrasonic treatment is performed, lecithin is added, filtration, rotary evaporation concentration, and vacuum freeze drying are performed to achieve uniform mixing of chitosan and pretreated lactose with amoxicillin, and uniformly dispersed composite particles are formed by spray drying. Chitosan can improve the solubility and bioavailability of amoxicillin, and the pretreated lactose improves the dispersibility and stability of amoxicillin in the preparation, thereby improving the solubility and bioavailability of the drug, ensuring the uniform distribution and sustained release of the drug in the body, improving the efficacy, and reducing the frequency of administration and side effects;

[0027] 3. Through step S4, the coated microparticles are cured at 40°C and 75% relative humidity for 4 hours to improve the stability of the coating layer and the controllability of drug release. Combined with the use of plasticizers in step S1, the plasticizer glycerol forms hydrogen bonds with the polymer chains through the hydroxyl groups in its molecular structure, reduces cohesion and enhances interchain sliding, plays a plasticizing role, and realizes the combination of curing treatment and plasticizer use, further improves the stability of the coating layer, and increases the flexibility and processing performance of the polymer. The curing treatment ensures the stability of the drug during storage and transportation. The plasticizer improves the mechanical strength and thermal stability of the preparation, ensuring that the drug can be released quickly and accurately when necessary, while remaining stable under conventional storage conditions. The enhanced mechanical strength and thermal stability make the preparation more reliable during use, improving the patient's medication safety and compliance. DETAILED DESCRIPTION

[0028] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0029] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0030] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0031] Preparation Example of Pretreated Lactose

[0032] Preparation Examples 1 to 5

[0033] The following is an explanation using Preparation Example 1.

[0034] In this preparation example, lactose was dissolved in an appropriate amount of deionized water, the lactose accounting for 5wt% of the mass of the deionized water, citric acid was added according to a mass ratio of citric acid to lactose of 1:10, and stirred until completely dissolved. The solution was placed in an ultrasonic processor and subjected to ultrasonic treatment for 30 minutes; wherein the ultrasonic frequency was set to 30kHz and the power was 300W;

[0035] 1.0 wt % of lecithin particles were added to the lactose-citric acid solution, stirring was continued for 30 minutes, and the lactose-citric acid-lecithin solution was filtered through a vacuum filtration device to remove undissolved impurities and large particles;

[0036] The filtrate was concentrated to 1 / 3 of the original volume using a rotary evaporator at a temperature below 50°C to further increase the concentration of the solution, and the concentrated solution was placed in a vacuum freeze dryer for freeze drying; wherein the freeze drying conditions were set as follows: freezing temperature -40°C, drying temperature -20°C, vacuum degree 0.01 mbar, and drying time 24 hours;

[0037] The dried powder is placed in a high-speed centrifuge and centrifuged at 10,000 rpm for 30 minutes to further remove possible free nanoparticles to ensure the purity of the final product; the dried lactose-citric acid-lecithin complex is crushed into a uniform fine powder by grinding or mechanical crushing, and sieved using sieves of different mesh sizes to ensure uniform particle size.

[0038] As shown in Table 1, the difference between Preparation Examples 1-5 is that the mass percentage (W1%) of lactose in deionized water is different.

[0039] Table 1

[0040] sample Preparation Example 1 Preparation Example 2 Preparation Example 3 Preparation Example 4 Preparation Example 5 W1％ 5 6 7 8 9

[0041] Example

[0042] In the following examples and comparative examples, when the content of components other than deionized water in the solution changes or new components are added, the weight of the solution is still supplemented to 100% by deionized water.

[0043] Examples 1-5

[0044] The following description is given by taking Example 1 as an example.

[0045] Example 1

[0046] The preparation method of the amoxicillin preparation in this embodiment comprises the following steps:

[0047] (1) preparing a temperature-sensitive polymer solution: dissolving PNIPAM in deionized water, wherein the PNIPAM accounts for 15 wt % of the mass of the deionized water, adding MBAA, wherein the mass ratio of PNIPAM to MBAA is 10:1, stirring evenly to form a uniform temperature-sensitive polymer solution, then adding glycerol, and continuing stirring to ensure uniform mixing;

[0048] (2) mixing the amoxicillin powder, chitosan and pretreated lactose (Preparation Example 1) uniformly, wherein the mass ratio of the amoxicillin powder, chitosan and pretreated lactose is 9:1:1, and then gradually adding the mixture to the temperature-sensitive polymer solution, continuing to stir to ensure uniform dispersion, and spray drying the mixed solution by spray drying to form amoxicillin-polymer composite particles;

[0049] (3) coating the amoxicillin-polymer composite microparticles using a fluidized bed to form a multi-layer temperature-sensitive coating layer;

[0050] (4) The coated microparticles were cured at 40° C. and 75% relative humidity for 4 hours to improve the stability of the coating layer and the controllability of drug release.

[0051] As shown in Table 2, the difference between Examples 1-5 is that different preparation examples are added in step (2).

[0052] Table 2

[0053] sample Example 1 Example 2 Example 3 Example 4 Example 5 Preparation Example Preparation Example 1 Preparation Example 2 Preparation Example 3 Preparation Example 4 Preparation Example 5

[0054] Examples 6 to 10

[0055] The difference between this embodiment and embodiment 1 is that PNIPAM accounts for the mass of deionized water.

[0056] As shown in Table 2, the difference between Examples 6-10 and Example 1 is that the mass of PNIPAM in deionized water is different (W2%).

[0057] Table 2

[0058] sample Example 6 Example 7 Example 8 Example 9 Example 10 W2％ 16 17 18 19 20

[0059] Comparative Example

[0060] Comparative Example 1

[0061] The difference between this comparative example and Example 1 is that the amoxicillin powder is uniformly mixed with chitosan and pretreated lactose, is not added into the temperature-sensitive polymer solution, and is directly spray-dried.

[0062] Comparative Example 2

[0063] The difference between this comparative example and Example 1 is that in this comparative example, MBAM is not added to the temperature-sensitive polymerization solution.

[0064] Comparative Example 3

[0065] The difference between this comparative example and Example 1 is that chitosan is not added in this comparative example.

[0066] Comparative Example 4

[0067] The difference between this comparative example and Example 1 is that an equal amount of pretreated lactose is replaced with lactose.

[0068] Comparative Example 5

[0069] The difference between this comparative example and Example 1 is that after spray drying, no fluidized bed coating treatment is performed, and the next step of solidification treatment is directly performed.

[0070] Performance Testing

[0071] In vitro dissolution test

[0072] Add an appropriate amount of 0.1N hydrochloric acid or pH 6.8 phosphate buffer to the USP dissolution apparatus, adjust the temperature to 37°C, place the amoxicillin preparation sample (tablet or capsule) into the dissolution medium, set the speed to 50 rpm, start the dissolution apparatus, take samples at predetermined time points (0, 10, 20, 30, 60, 120, 180 minutes), the sampling volume is about 5 ml, use HPLC to detect the concentration of amoxicillin solution at each time point, and the experimental data of the test are shown in Table 3.

[0073] Table 3

[0074]

[0075]

[0076] Combining Examples 1 to 10 and Table 1, it can be seen that within the first 30 minutes, the amoxicillin release rate of Examples 1-10 is relatively fast, indicating that the preparations can quickly release the drug in the initial stage and quickly reach an effective concentration. At 180 minutes, the release amount of amoxicillin is close to or reaches 50 mg / L, indicating that these preparations can accurately release the drug to meet the treatment needs; within the first 60 minutes, the release rate of Example 8 is the highest, indicating that the formula and process of Example 8 have advantages in improving the drug release rate. As the PNIPAM content increases in Examples 6-10, the cumulative drug release amount does not change much, indicating that within a certain range, the effect of PNIPAM content on drug release is not significant;

[0077] It can be seen from Example 1, Comparative Example 1 and Table 1 that the dissolution concentration of the amoxicillin preparation prepared in Comparative Example 1 is lower than that of the amoxicillin preparation prepared in Example 1, indicating the importance of temperature-sensitive polymers in rapid drug release.

[0078] Combining Example 1, Comparative Example 2 and Table 1, it can be seen that the dissolution concentration of the amoxicillin preparation prepared in Comparative Example 2 is lower than that of the amoxicillin preparation prepared in Example 1, which illustrates the role of the cross-linking agent MBAA in enhancing drug release control and stability.

[0079] It can be seen from Example 1, Comparative Example 3 and Table 1 that the dissolution concentration of the amoxicillin preparation prepared in Comparative Example 3 is lower than that of the amoxicillin preparation prepared in Example 1, which illustrates the role of chitosan in improving drug solubility and bioavailability.

[0080] It can be seen from Example 1, Comparative Example 4 and Table 1 that the dissolution concentration of the amoxicillin preparation prepared in Comparative Example 4 is lower than that of the amoxicillin preparation prepared in Example 1, which illustrates the role of pre-treated lactose in improving the dispersibility and stability of the drug.

[0081] Combining Example 1, Comparative Example 5 and Table 1, it can be seen that the dissolution concentration of the amoxicillin preparation prepared in Comparative Example 5 is lower than that of the amoxicillin preparation prepared in Example 1, which illustrates the role of coating treatment in controlling drug release and improving drug stability.

[0082] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing an amoxicillin preparation, characterized in that: The steps include: S1. Prepare a temperature-sensitive polymer solution: dissolve PNIPAM in deionized water, add MBAA, stir evenly to form a uniform temperature-sensitive polymer solution, then add a plasticizer, and continue stirring to ensure uniform mixing; S2. The amoxicillin powder is mixed with chitosan and pretreated lactose, and then gradually added to the temperature-sensitive polymer solution, and stirring is continued to ensure uniform dispersion, and the mixed solution is spray-dried by a spray drying method to form amoxicillin-polymer composite particles; S3. Amoxicillin-polymer composite microparticles are coated using a fluidized bed to form a multi-layer temperature-sensitive coating layer; S4. The coated microparticles were cured at 40° C. and 75% relative humidity for 4 hours to improve the stability of the coating layer and the controllability of drug release.

2. The method for preparing the amoxicillin preparation according to claim 1, characterized in that: The plasticizer is glycerol.

3. The method for preparing the amoxicillin preparation according to claim 1, characterized in that: In step S2, the lactose pretreatment step includes the following: Dissolve lactose in an appropriate amount of deionized water, add citric acid at a mass ratio of 1:10 between citric acid and lactose, stir until completely dissolved, place the solution in an ultrasonic processor, and perform ultrasonic treatment for 30 minutes; wherein the ultrasonic frequency is set to 20-40kHz and the power is 200-400W; Add 0.5-2wt% of lecithin particles to the lactose-citric acid solution, continue stirring for 30 minutes, and filter the lactose-citric acid-lecithin solution through a vacuum filtration device to remove undissolved impurities and large particles; The filtrate was concentrated to 1 / 3 of the original volume using a rotary evaporator at a temperature below 50°C to further increase the concentration of the solution, and the concentrated solution was placed in a vacuum freeze dryer for freeze drying; wherein the freeze drying conditions were set as follows: freezing temperature -40°C, drying temperature -20°C, vacuum degree 0.01 mbar, and drying time 24 hours; The dried powder is placed in a high-speed centrifuge and centrifuged at 10,000 rpm for 30 minutes to further remove possible free nanoparticles to ensure the purity of the final product; the dried lactose-citric acid-lecithin complex is crushed into a uniform fine powder by grinding or mechanical crushing, and sieved using sieves of different mesh sizes to ensure uniform particle size.

4. The method for preparing the amoxicillin preparation according to claim 3, characterized in that: Lactose is present in an amount of 5 to 9 wt % of the mass of deionized water.

5. The method for preparing the amoxicillin preparation according to claim 1, characterized in that: In step S1 , the mass ratio between PNIPAM and MBAA is 10:1, and PNIPAM accounts for 15 to 20 wt % of the mass of deionized water.

6. The method for preparing the amoxicillin preparation according to claim 1, characterized in that: In step S2, the mass ratio of amoxicillin powder, chitosan and pretreated lactose is 9:1:

1.

7. An amoxicillin preparation prepared by the preparation method according to any one of claims 1 to 6, characterized in that: The outer side of the amoxicillin preparation is coated with multiple temperature-sensitive coating layers.

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